Aporphine esters and their use in therapy

Abstract

New aporphine derivatives are disclosed which have formula (I) and the physiologically acceptable salts thereof. Said derivatives may be used for the treatment of Parkinson's disease, hemicrania, restless legs syndrome (RLS), sexual dysfunction in men and women, hyperprolactemia and psychotic disorders, and/or evaluation of Parkinson's disease. Processes for the preparation of such derivatives are also disclosed.

1. An aporphine derivative having formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 one of R 1  and R 2  is hydrogen or acetyl and the other one is selected from the group consisting of (C 3 –C 20 )alkenoyl; halo-(C 3 –C 20 )alkanoyl; (C 3 –C 20 )alkanoyl; (C 4 –C 7 )cycloalkanoyl; (C 3 –C 6 )-cycloalkyl(C 2 –C 16 )alkanoyl; aroyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (C 1 –C 3 )alkyl and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; aryl (C 2 –C 16 )alkanoyl which is unsubstituted or substituted in the aryl moiety by 1 to 3 substituents selected from the group consisting of halogen, (C 1 –C 3 )alkyl and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and hetero-arylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl moiety, said heteroaryl moiety being a five or six membered ring, and 2 to 10 carbon atoms in the alkanoyl moiety and which is unsubstituted or substituted in the heteroaryl moiety by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethane sulphonyloxy, (C 1 –C 3 )alkyl, and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and 
 R 3  is selected from the group consisting of hydrogen; (C 1 –C 4 )-alkyl, which is unsubstituted or substituted by 1 to 3 halogen atoms; cyclopropyl and cyclopropylmethyl, and the physiologically acceptable salts thereof. 
 
     
     
       2. An aporphine derivative according to  claim 1 , wherein one of R 1  and R 2  is hydrogen or acetyl and the other one is selected from the group consisting of (C 3 –C 20 )alkanoyl, (C 4 –C 7 )-cycloalkanoyl, benzoyl which is unsubstituted or substituted by a chlorine atom or 1 to 3 methoxy groups, phenylacetyl which may be substituted with a chlorine atom, and hetero-arylacetyl, and R 3  is (C 1 –C 3 )alkyl or cyclopropyl. 
     
     
       3. An aporphine derivative according to  claim 2 , wherein one of R 1  and R 2  is hydrogen and the other one is selected from the group consisting of propanoyl, propenoyl, butanoyl, iso-butanoyl, pivaloyl, decanoyl, hexadecanoyl, cyclopropanoyl and benzoyl and R 3  is methyl or propyl. 
     
     
       4. An aporphine derivative according to  claim 2 , wherein one of R 1  and R 2  is acetyl and the other one is selected from the group consisting of butanoyl, isobutanoyl, cyclopropanoyl, cyclohexanoyl, pivaloyl, decanoyl and hexadecanoyl and R 3  is methyl. 
     
     
       5. Process for the preparation of an aporphine mono-ester derivative having formula (I′) 
       
         
           
           
               
               
           
         
       
       wherein
 one of R′ 1  and R′ 2  is hydrogen and the other one is selected from the group consisting of acetyl, (C 3 –C 20 )alkanoyl; halo-(C 3 –C 20 )alkanoyl; (C 3 –C 20 )alkenoyl; (C 4 –C 7 )cycloalkanoyl; (C 3 –C 6 )-cycloalkyl(C 2 –C 16 )alkanoyl; aroyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (C 1 –C 3 )alkyl and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; aryl (C 2 –C 16 )alkanoyl which is unsubstituted or substituted in the aryl moiety by 1 to 3 substituents selected from the group consisting of halogen, (C 1 –C 3 )alkyl and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and heteroarylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl moiety, said heteroaryl moiety being a five or six membered ring, and 2 to 10 carbon atoms in the alkanoyl moiety and which is unsubstituted or substituted in the heteroaryl moiety by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (C 1 –C 3 )alkyl, and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and 
 R 3  is selected from the group consisting of hydrogen; (C 1 –C 4 )-alkyl, which is unsubstituted or substituted by 1 to 3 halogen atoms; cyclopropyl and cyclopropylmethyl; which process comprises 
 a) reacting an aporphine of formula (II), 
 
       
         
           
           
               
               
           
         
         wherein R 3  is defined as above, with an acid chloride of formula (III)
   R 4 —Cl 
 
         wherein R 4  is as defined for said other one of R′ 1  and R′ 2  above, in the molar ratio of aporphine to acid chloride of from 1:1 to 1:5 and in trifluoracetic acid and methylene chloride (CH 2 Cl 2 ); 
         b) after the reaction being completed, evaporating the solvents or lyophilizing the reaction mixture; 
         c) dissolving the residual crude product mixture in CH 2 Cl 2  and purifying by chromatography on Al 2 O 3  eluting with CH 2 Cl 2  and then with t-BuOH:CH 2 Cl 2  or EtOH:CH 2 Cl 2  mixtures in a stepwise gradient of increasing concentration of t-BuOH and EtOH, respectively, of from 1 to 15% by volume of the mixture, and isolating fractions containing the isomeric mono-ester derivatives of the formula (I′); and 
         d) separating said isomeric mono-ester derivatives of formula (I′) by known techniques to isolate a single mono-ester of the formula (I′). 
       
     
     
       6. Process for the preparation of an aporphine di-ester derivative having formula (I″) 
       
         
           
           
               
               
           
         
       
       wherein
 one of R″ 1  and R″ 2  is acetyl and the other one is selected from the group consisting of (C 3 –C 20 )alkanoyl; halo-(C 3 –C 20 )alkanoyl; (C 3 –C 20 )alkenoyl; (C 4 –C 7 )cycloalkanoyl; (C 3 –C 6 )cycloalkyl(C 2 –C 16 )alkanoyl; aroyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (C 1 –C 3 )alkyl and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; aryl (C 2 –C 16 )alkanoyl which is unsubstituted or substituted in the aryl moiety by 1 to 3 substituents selected from the group consisting of halogen, (C 1 –C 3 )alkyl and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and hetero-arylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl moiety and 2 to 10 carbon atoms in the alkanoyl moiety and which is unsubstituted or substituted in the heteroaryl moiety by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (C 1 –C 3 )alkyl, and (C 1 –C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and 
 R 3  is selected from the group consisting of hydrogen; (C 1 –C 4 )-alkyl, which is unsubstituted or substituted by 1 to 3 halogen atoms; cyclopropyl and cyclopropylmethyl; which process comprises 
 a) reacting an aporphine mono-ester of formula (I′) 
 
       
         
           
           
               
               
           
         
         wherein 
         one of R′ 1  and R′ 2  is hydrogen and the other one is acetyl and R 3  is as defined above, with an acid chloride of the general formula (IV)
   R 5 —Cl 
 
         wherein R 5  is as defined for said other one of R″ 1  and R″ 2  above, in the molar ratio of aporphine mono-ester to acid chloride of from 1:1 to 1:5 and trifluoracetic acid and methylene chloride (CH 2 Cl 2 ); 
         b) after the reaction being completed, evaporating the solvents or lyophilizing the reaction mixture; 
         c) dissolving the residual crude product mixture in CH 2 Cl 2  and purifying by chromatography on Al 2 O 3  eluting with CH 2 Cl 2  and then with t-BuOH:CH 2 Cl 2  and EtOH:CH 2 Cl 2  mixtures in a stepwise gradient of increasing concentration of t-BuOH and EtOH, respectively of from 1 to 15% by volume of the mixture, and isolating fractions containing the isomeric di-ester derivatives of the formula (I″); and 
         d) separating said isomeric di-ester derivatives of formula (I″) by known techniques to isolate a single di-ester of the formula (I″). 
       
     
     
       7. A pharmaceutical composition comprising as an active principle at least one aporphine derivative of formula I as identified in  claim 1  or a physiologically acceptable salt thereof together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
       8. A pharmaceutical composition according to  claim 7 , which is in the form of a patch or ointment for transdermal administration. 
     
     
       9. A pharmaceutical composition according to  claim 8 , which furthermore comprises stabilizers, solubilizers and permeation activators to facilitate the passage of the active principle through the skin. 
     
     
       10. A pharmaceutical composition according to  claim 7 , which is in the form of a depot preparation for subcutaneous or intramuscular administration comprising said aporphine derivative of formula I or the physiologically acceptable salt thereof dissolved or suspended in an oil. 
     
     
       11. A pharmaceutical composition according to  claim 10 , which in addition to the aporphine derivative of formula I or the physiologically acceptable salt thereof contains a local anesthetic. 
     
     
       12. A pharmaceutical composition according to  claim 7 , which is in a form suited for oral, sublingual, pulmonary, rectal, vaginal or intraduodenal administration. 
     
     
       13. A phannaceutical composition according to  claim 7 , which in addition to the aporphine derivative of formula I or the physiologically acceptable salt thereof contains an effective amount of an anti-emetic agent. 
     
     
       14. A process for manufacturing a medicament, said process comprising contacting an aporphine derivative of formula I as identified in  claim 1  or a physiologically acceptable derivative thereof with a pharmaceutically acceptable carrier. 
     
     
       15. Method for the treatment of Parkinson's disease or hyperprolactemia, comprising administering to a subject in need of such a treatment of a therapeutically effective amount of an aporphine derivative of the formula I as defined in  claim 1  or of a physiologically acceptable salt thereof. 
     
     
       16. The process of  claim 5  wherein said step of dissolving the residual crude product mixture in CH 2 Cl 2  and purifying by chromatography on Al 2 O 3  eluting with CH 2 Cl 2  and then with t-BuOH:CH 2 Cl 2  or EtOH:CH 2 Cl 2  mixtures in a stepwise gradient of increasing concentration of t-BuOH and EtOH, respectively, of from 2 to 10% by volume, of the mixture, and isolating fractions containing the isomeric mono-ester derivatives of the formula (I′). 
     
     
       17. The process of  claim 6  wherein said step of dissolving the residual crude product mixture in CH 2 Cl 2  and purifying by chromatography on Al 2 O 3  eluting with CH 2 Cl 2  and then with t-BuOH:CH 2 Cl 2  and EtOH:CH 2 Cl 2  mixtures in a stepwise gradient of increasing concentration of t-BuOH and EtOH, respectively of from 2 to 10% by volume of the mixture, and isolating fractions containing the isomeric di-ester derivatives of the formula (I″).